Alzheimer's disease (AD) will soon become a public health crisis. There currently are no treatments that delay the onset or prevent the progression of AD, though several promising candidates are in development. It will, therefore, be important to have biomarkers that can identify individuals at high risk in order to target them for clinical trials, disease-modifying therapies and to monitor therapy. AD pathology (e.g., A(3 plaques) begins 10-20 years before the onset of cognitive symptoms. Even the earliest clinical symptoms are accompanied by neuronal and synaptic dysfunction/death. Thus, it will be critical to identify individuals with "preclinical" AD, prior to marked clinical symptoms and neuron loss, so new therapies will have the best chance to preserve normal brain function. Low levels of CSF AP42 have been shown to be an excellent marker of cortical amyloid early in the disease, whereas CSF tau/AP42 and ptaui8i/AP42 ratios are useful in predicting future cognitive decline. It is unclear, however, how early in the disease process such changes in CSF become detectable, so efforts are being made to study younger cohorts in the hopes of identifying affected individuals at the very earliest stages. Our long term goal is to fully understand the longitudinal evolution of biomarker changes during the natural course of AD. Project 2 begins to address this goal. Aim 1: Obtain standardized measures of Ap4o, AP42, tau, ptaui8i, and novel markers YKL-40, and VILIP-1 in fasted CSF samples and APi^o, Apx-40, Api^2, and APx-42in matched, fasted plasma samples using enzymelinked immunosorbent assays (plate-based ELISA) and xMAP (Luminex, bead-based) technologies. Aim 2: In longitudinal studies, assess the annual rate of change in biomarker levels as a function of family history and APOE e4 status, and investigate whether low CSF AP42 levels, or a drop in AP42 over time, predict future change in other biomarker analytes, such as tau, ptauisi, neuroinflammatory markers (e.g.,YKL-40), or putative markers of neurodegeneration (e.g., VILIP-1). Aim 3: Correlate fluid biomarker measures (and rate of biomarker change over time) with future cognitive decline (Clinical Core), changes in cortical amyloid load as assessed by PIB (Project 1), neuropsychological measures (Project 3), and structural/functional neuroimaging measures (Project 4).